We have recently demonstrated that 7-amine substituted analogs of actinomycin D (AMD), in spite of bulky substitution, can bind efficiently to DNA and exhibit inhibitory properties against P388 mouse tumors in vivo, comparable to in some instance superior to AMD itself. We have also found that appropriate substitents on N2 of AMD and 07 of 7-hydroxy AMD show strong DNA binding and biological growth inhibitory properties. Despite the previously reported sensitivity of AMD to nearly all chemical manipulation and consequent loss of biological activity, it is now clear that the antitumor properties can be improved and broadended by well-defined substitution on the chrompohore of AMD. We now propose a concerted chemical and biochemical approach amined at exploring AMD resistance of known tumor lines and development of novel analogs of AMD, hopefully with a broader spectrum of tumor specificity. The chemical studies will involve substitution at the N2,7, and possibly 8 positions of AMD. The biochemical studies will include the relative uptake and retention and metabolism of the analogs compared to AMD by defined tumor cells in culture either sensitive or resistant to AMD. Simultaneously, inhibition of nucleic acid synthesis, nuclear and DNA binding properties and testing of the growth inhibitory properties of analogs in a number of in vitro and in vivo biological systems will be carried out. In addition, inherent fluorescence and radioactivity of selected synthetic radiolabelled analogs will facilitate the cell localization and transport sutdies. The ultimate objective is to produce an agent with a broader spectrum of antitumor activity against human neoplasia.